Mu-opioid receptors are therapeutic targets for many addictive disorders since they are key components for mediating the rewarding effects of opiates, nicotine, cannabinoids, alcohol and food. The renewal of the UCLA Center for Opioid Receptors and Drugs of Abuse (CSORDA) will focus on the circuitry and cell-specific adaptations underlying addiction-related behaviors mediated by mu opioid receptors. The center will investigate hedonic control and reinforcement learning as well as dysphoria and relapse following abstinence of both opiate drugs and substances reliant on endogenous opioid circuitry to elicit reward. The research plan will build upon progress during the past funding period by incorporating several CSORDA-developed innovative genetic mouse models that selectively lack, or selectively rescue, mu-receptors in discrete cell-types and brain regions, and knock-in mice expressing fluorescently labeled mu receptors. CSORDA advances in instrumental behavior, including the measurement of liking and wanting, self-administration of opioids, as well as models of dysphoric states, will provide synergistic analysis of addictive behaviors mediated by specific mu opioid receptor circuits. Four Research Components are proposed that are highly interactive both thematically and technically and that use shared models and reagents. A principle focus will be the central roles played by mu-opioid receptors in striatal sub regions (striosome/patch and matrix) and neuron sub-populations in addiction-related behaviors, including the relationship to dopamine transmission, and cellular and molecular adaptations in response to opioids (Components I, III and IV). With evidence for dopamine-independent mechanisms for mu-mediated reward, the contribution of extrastriatal mu-opioid receptors will also be assessed (Components II, III and IV) with a specific focus on the habenular complex, where mu-opioid receptor expression is the highest in the CNS. The research will employ mouse genetics and behavioral analysis combined with electrophysiology, optogenetics, single cell transcript analysis and epigenetics. CSORDA will support an Epigenetic/Transcriptome Profiling Core, and an Animal Breeding Core supplying all CSORDA Components with mouse models and extending facilities into the research community. The Administrative Core and CSORDA Advisory board, consisting of Drs. Balleine, Bonci, Koob, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a Pilot Program for the center.